Formation of a carbon-carbon bond remains one of the most important reactions in organic chemistry and has applications in a variety of fields including medicinal chemistry, agricultural chemistry, polymer chemistry and material science. While many carbon-carbon bond forming reactions involve an electrophile (e.g., carbonyl compound) and a nucleophile (e.g., organometallic compound), others require the presence of a coupling catalyst.
One particularly useful nickel catalyzed reaction involves coupling an organometallic compound (e.g., Grignard reagent) with enol ethers or aryl ethers. See Wenkert et al., J. Amer. Chem. Soc., 1979, 101, 2246 and Wenkert et al., J. Org. Chem., 1984, 49, 4894. Wenkert et al. report using bis(triphenylphosphine)nickel dichloride or [1,3-bis(diphenylphosphino)propane]nickel dichloride catalyst in an aromatic solvent such as toluene and benzene. However, there are many limitations to these reactions. For example, although the reaction between a methoxy substituted naphthalene compound and phenylmagnesium halide is relatively efficient, a coupling reaction between a methoxy substituted phenyl compound (e.g., anisole derivative) is significantly lower. Furthermore, aryl ethers are “inert to [substitution by] methylmagnesium bromide.” See Wenkert et al., J. Amer. Chem. Soc., 1979, 101, 2246 at 2247.
Moreover, some aromatic solvents such as benzene are highly carcinogenic. Thus, the use of these solvents increases the cost of the overall process due to disposal and safe handling requirements. In addition, in some instances it is difficult to remove all traces of these highly carcinogenic solvents. Hence, the use of these solvents in the preparation of products that are directly utilized or consumed by humans (e.g., therapeutics) is discouraged or prohibited.
There remains a need for a catalyst that is effective and more efficient in forming a carbon-carbon bond between a non-activated aromatic ether, including heteroaryl ether, and an alkyl or aryl organometallic compound. There is also a need for a catalyst that does not require the use of an aromatic solvent in a coupling reaction.